Intramolecular chiral induction

As described hitherto, diastereoselectivity is controlled by the stereogenic center present in the starting material (intramolecular chiral induction). If these chiral substrates are hydrogenated with a chiral catalyst, which exerts chiral induction intermolecularly, then the hydrogenation stereoselectivity will be controlled both by the substrate (substrate-controlled) and by the chiral catalyst (catalyst-controlled). On occasion, this will amplify the stereoselectivity, or suppress the selectivity, and is termed double stereo-differentiation or double asymmetric induction [68]. If the directions of substrate-control and catalyst-control are the same this is a matched pair, but if the directions of the two types of control are opposite then it is a mismatched pair. 

Within a helicate, all of the metal centers are homoconfigurational. Intramolecular chiral induction through the incorporation of enantiomerically pure ligands effectively leads to enantio-merically pure helicates. There have also been reports of the separation and enrichment of racemic helicates synthesized from achiral ligands. In a rare example, spontaneous resolution of trinuclear triple-stranded helicates was observed. Williams and co-workers have produced helicates with labile Co , which allowed rapid racemization of the enantiomers. Subsequent oxidation of the metal centers to inert Co locked the helical twist and allowed for chiral... 

One factor in favor of the induction of observable chirality is the effect of chiral amplification [ 111,112]. This is also known as the sergeants and soldiers effect [111]. These effects can be either intramolecular or intermolecular [113], and is often the result of complex equilibria [114]. The article by Masu et al. reflects the problem of chiral induction. They found that the 5-phenylethyl group was not sufficient to induce a measurable population difference between the two helix forms, while the 5-napthylethyl group was [103]. Many experiments have been reported including the addition of chiral side chains which allows CD spectroscopy to be used, seclusion of chiral hosts into the cavity created by helix formation, chiral salts around the helix, EPR, and solid state x-ray studies [3,67,115,116]. A direct comparison between intermolecular and intramolecular chiral induction was possible in the case of a pyridinecar-boxamide system where the intramolecular induction was considerably more effective [113]. 

Slgmatropic rearrangement with H-transler and C-C txjrxJ formation (inter or intramolecular) and chiral induction... 

Asymmetric induction and stereoregularity can be treated, at least in part, as two distinct phenomena however, it has been observed that the values of pu and Pol can be divided into two parts one dependent on chiral factors external to the chain (catalyst, environment, etc.) and the other dependent on the intramolecular chain induction. This latter is a factor of stereoregularity or cooper-ativity rather than of chirality (its value is identical for both the DD and LL successions) (328). Both factors can be expressed as differences of free energies of activation In favorable cases, when they are of the same sign, asymmetric polymerization becomes easier (i.e., under the same conditions it gives a higher optical yield) than an analogous nonmacromolecular asymmetric synthesis. 

The bislactim ether method has also been applied to an intramolecular alkylation (84JOC2286) to generate stereospecifically the /3-tum-inducing element, (LL) 3-amino-2 piperidone-6-carboxylic acid as shown in Scheme 62. The efficiency of chiral induction was in the range 99.5%. It is noteworthy that there is no racemization of the intermediate bromo compound, thus proving the regiospecificity of the deprotonation. 

The use of ketocarbenoids with chiral auxiliaries has not been terribly effective at chiral induction. Menthol and bomeol esters of diazoacetates resulted in very low enantioselectivity.38 Some improvements were obtained by using the chiral amide (29 equation 13), but low overall yields were obtained due to competing intramolecular side reactions.39 Related studies with other types of carbenoids, however, have resulted in high enantioselectivity.60... 

Scheme 25 Chiral induction in the intramolecular reaction of ketenimines (102a,b) and (104)...

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Intramolecular oxidative cyclizations in the appropriately substituted phenols and phenol ethers provide a powerful tool for the construction of various practically important polycyclic systems. Especially interesting and synthetically useful is the oxidation of the p-substituted phenols 12 with [bis(acyloxy)iodo]-arenes in the presence of an appropriate external or internal nucleophile (Nu) leading to the respective spiro dienones 15 according to Scheme 6. It is assumed that this reaction proceeds via concerted addition-elimination in the intermediate product 13, or via phenoxenium ions 14 [18 - 21]. The recently reported lack of chirality induction in the phenolic oxidation in the presence of dibenzoyltar-taric acid supports the hypothesis that of mechanism proceeding via phenoxenium ions 14 [18]. The o-substituted phenols can be oxidized similarly with the formation of the respective 2,4-cyclohexadienone derivatives. 

Disubstituted cyclopentane-1,3-diones and cyclohexane-1,3-diones were used as substrates. After formation of the aldol adducts subsequent intramolecular dehydration furnished products of types 94 and 96. The asymmetric intramolecular aldol reaction proceeds with a broad variety of natural amino acids as organocata-lysts. Among these L-proline was usually found to be the most versatile. For example, conversion of the 2,2-disubstituted cyclopentane-1,3-dione 93 in the presence of L-proline gave the desired product 94 in 86.6% yield and with enantioselectivity of 84% ee [97]. This example and a related reaction with a 2,2-disubstituted cyclohexane-1,3-dione 95 are shown in Scheme 6.42. Chiral induction depends... 

The mechanism of the [3 + 2] cycloaddition is summarized in Scheme The first intermediate results from charge transfer interaction between the eli tronically excited aromatic compound at its singlet state S1 with the alkene w] leads to the formation of the exciplexes K. A more stable intermediate is generated by the formation of two C-C bonds, leading to the intermediates These intermediates have still singlet multiplicity and therefore possess zwii ionic mesomeric structures mainly of type M. In most cases and especially intramolecular reactions, chiral induction occurs during the formation of L. final products are then obtained by cyclopropane formation in the last step. 

It is interesting that anodic methoxylation and subsequent chemical alkylation of optically active V-protected a-amino acids with one more chiral center affords the final products in high optical purity, although the diastereomeric purity of the intermediate methoxylated products does not seem to be so high [405,406]. Intramolecular asymmetric induction may occur in the chemical alkylation step. 

Intramolecular asymmetric induction has also been used in electrochemistry as in the reduction of optically active alcohol esters or amides of a-keto [469,470] and unsaturated [471] acids and oximes [472] and in the oxidation of olefins [473]. A maximum asymmetric yield of 81% was obtained in the reduction of (5 )-4-isopropyl-2-oxazolidinone phenyl-glyoxylate [470]. Nonaka and coworkers [474,475] found that amino acid A-carboxy anhydrides were polymerized with various electrogenerated bases as catalyst to give the poly(amino acids) with high chirality in high yields. Conductive chiral poly(thiophenes) prepared by electropolymerization can be used for chiral anion recognition [476]. 

The BINAP-Ru-catalyzed hydrogenation of the allylic alcohol 94 results in the diastereoselective formation of 95, an intermediate for 1/9-methylcarbapenems (96) possessing an improved stability toward dehydropeptidase (Scheme 28). The combined effects of tbe intermolecular asymmetric induction caused by the (/ )-Tol-BINAP-Ru catalyst (Tol-BINAP = p-tolyl analog of BINAP) and the intramolecular asymmetric induction originating from the pre-existing chiral moiety in the substrate 94 cooperate in the generation of the extremely high diastereos-electivity, /5 a = 99.9 0.1, to form the y8-methylated isomer 96 [87]. 

Diastereoselective hydrogenation with BINAP-Ru combines chirality transfer from the catalyst and intramolecular asymmetric induction, providing an efficient entry to statine analogues ... 

An example of efficient chiral induction in a photoreaction is provided by the irradiation of inclusion compounds of pyridones (11) with the chiral host (10) (Tanaka et al, Chapter 2). This process afforded optically active p-lactams (12) with ee in the range 91-99%. The intramolecular 2 4-2 alkene photocycloaddition of (13) catalysed by Cu(I) afforded the tricyclic compound (14) in 89% yield,... 

Thermal or catalytic sigmatropic rearrangement with H-transfer and C-C bond formation either inter or intramolecular and with chiral induction (see 1st edition). 

Asymmetric halolactonization is a much used procedure for the stereoselective formation of C — Br and C —I bonds (see also Sections D.4.6. and D.7.2.). This intramolecular reaction is used to transfer chiral information in the molecule over three or four bonds, sometimes with high stereoselectivity. Formation of a halonium complex with the olefin is the first step of the reaction followed by intramolecular lactonization. Induction of asymmetry is achieved in different ways. 

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